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Phosphatidylcholine translocase: un papel fisiológico para el gen mdr2

S Ruetz¹, P Gros

¹Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

|July 1, 1994

Resumen

La P-glicoproteína (P-gp) del ratón mdr2 funciona como una flipasa lipídica en las vesículas secretoras de la levadura. Esta actividad de la lipidotranslocasa es dependiente del ATP y específica de la fosfatidilcolina, a diferencia del mdr3 P-gp.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
Biología celular Biología celular.

Sus antecedentes:

Las glicoproteínas P (P-gps) son transportadores de cassette de unión al ATP involucrados en la resistencia a múltiples fármacos.
Su papel en el transporte de lípidos, particularmente como translocaciones de lípidos o flippases, es un área de investigación activa.
Comprender la función de P-gp es crucial para el desarrollo de fármacos y la homeostasis de lípidos celulares.

Objetivo del estudio:

Para investigar la actividad lipídica translocasa/flippasa de las glicoproteínas P de los ratones mdr2 y mdr3.
Caracterizar las diferencias funcionales entre mdr2 y mdr3 P-gps en un sistema heterólogo.
Desarrollar y utilizar un ensayo para cuantificar la asimetría lipídica en las vesículas secretoras de levadura.

Principales métodos:

Expresión de los genes mdr2 y mdr3 del ratón en las vesículas secretoras (VS) de la levadura mutante sec6-4 .
Desarrollo de un ensayo analógico fluorescente de fosfatidilcolina (PC) para medir la distribución de lípidos en las bicapas de las vesículas.
Análisis de la translocación de PC al prospecto interno de SVs bajo diversas condiciones (tiempo, temperatura, ATP, Mg2+, inhibidores, moduladores).

Principales resultados:

La expresión de Mdr2 en SVs de levadura mejoró significativamente la translocación de fosfatidilcolina (PC) al prospecto interno de una manera dependiente del tiempo y la temperatura.
La expresión de Mdr3 no afectó a la distribución de PC, lo que indica la especificidad del efecto mediado por mdr2.
La translocación de PC mediada por mdr2 fue dependiente del ATP y Mg2+, inhibida por el vanadato y el verapamil, pero no afectada por la colchicina o la vinblastina.

Conclusiones:

El ratón mdr2 P-glicoproteína funciona como una translocación lipídica (flippase) para la fosfatidilcolina en las vesículas secretoras de la levadura.
Mdr2 exhibe una actividad específica de transporte de lípidos distinta de la de mdr3.
La actividad de mdr2 P-gp como una flipasa es dependiente de ATP y modulada por inhibidores específicos y verapamil, consistente con su naturaleza P-gp.

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